Studies in collaboration with Drs. W.J. Leonard and M. Noguchi (NHLBI) have resulted in localization of the interleukin 2 gamma receptor gene on the human X-chromosome. Mapping in human-rodent somatic cell hybrids combined with in situ hybridization and genetic linkage analysis using single strand conformational polymorphisms within introns of the IL- 2Rgamma gene allowed this gene to be localized to band Xql3, and it was shown to be tightly linked to PGK1 and anonymous DNA markers including DXS1O6. The disease locus for X-linked Severe Combined Immunodeficiency (XSCID) is linked to these same loci, strongly suggesting that XSCID may involve mutations in the IL-2Rgamma gene. This interpretation subsequently has been confirmed by our collaborators (Noguchi and Leonard) who demonstrated that each of three unrelated patients with XSCID has a different mutation in his IL-2Rgamma gene resulting in a different premature stop codon and C-terminal truncation. Further studies are in progress to optimize carrier detection and gene therapy. Cloned genes recently mapped include a phosphotyrosine phosphatase (PAC) with K. Kelly, a plasma membrane Ca2+ ATPase isoform 3 (PMCA3) with E. Carafoli, and two additional transglutaminases (TGM2 & TGM3) with P. Steinert; about 12-15 additional genes are currently being mapped. A third project has involved identification and sequencing of DNA tracts containing highly polymorphic short tandem repeats. A group of ten of these loci containing triplet repeats have been isolated and they provide a useful panel of microsatellites for mapping disease genes on human chromosome 22 and these ordered loci span an interval of 70 cM on this chromosome.
